This proposal is for a pathway to independence award. The candidate will learn new techniques and create a divergent research focus from the mentor lab. The candidate's primary goal is to become an independent investigator and make major scientific contributions to the neurodegenerative disease research field. A detailed career development plan that includes coursework, learning new techniques, scientific meeting attendance, and specific feedback from an advisory committee has been constructed to help the candidate achieve this goal. The research focus of this proposal is on gene-environment interactions in Parkinson's disease (PD). New approaches to modeling such interactions are a major focus of this proposal. The causes of most PD cases are unknown - ~10% are inherited. The causes of the remaining 'sporadic' ~90% are unknown. Epidemiological evidence has repeatedly suggested that environmental exposures increase the risk for PD. However, no single toxicant has been identified as a causative agent. Most cases may arise from both environmental and genetic factors. However, such interactions are poorly understood. Research to date on gene-environment interactions has typically utilized toxicant models that have little relevance to human health. Indeed, current PD models have major etiological limitations. Toxicant models typically use large acute doses by unrepresentative routes of exposure and genetic models often use complete life-span knockout of a gene or massive transgene expression. I hypothesize that: 'early-stage' environmental PD modeling is best suited to study gene-environment interactions. I propose to overcome current barriers by: Aim1) Creating both 'early' and 'late' stage PD models using relevant environmental toxicants. Here, toxicants recently linked to PD will be used to create new rodent models that reproduce the key features of both early and late-stage PD and utilize environmentally relevant toxicants. This aim will serve as a 'screen' to identify the optimal toxicant model to advance to later aims. The toxicant producing the best model will move forward to later aims. Aim 2) 'Real-world' exposure modeling. This aim will utilize toxicant exposure through dosing regimens that bear relevance to human health. Aim 3) Creating new gene-environment interaction models. Here, transgenic rats expressing mutations known to cause PD in humans will be exposed to the optimal toxicant from aim 1. Thus a new gene-environment rodent PD model will be created that utilizes an environmental toxicant linked to PD and expresses a mutation known to cause human PD. Brain toxicant levels will be determined and correlated with pathological observations (Aims 1-3). Aim 4) Testing gene therapy approaches in these models. In vivo modulation of PD genes will be tested as a potential therapeutic approach in newly created toxicant models. This project is expected to produce major advances in gene-environment interaction modeling. Newly created models will be used to identify pathogenic pathways and test new therapeutic approaches.